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Albumin-Embellished Arsenic Trioxide-Loaded Polymeric Nanoparticles Enhance Tumor Accumulation and Anticancer Efficacy via Transcytosis for Hepatocellular Carcinoma Therapy

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  • Theme: Recent Advances on Drug Delivery Systems for Viral Infections
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Abstract

Arsenic trioxide (ATO) has efficient anticancer effect on hepatocellular carcinoma (HCC) in clinical trials, but its off-target distribution and side effects have limited its use. Here, we demonstrate an albumin-embellished ATO-loaded polyethylene glycol–polycaprolactone–polyethyleneimine (PEG–PCL–PEI) nanoparticle (AATONP) to enhance the tumor distribution and intratumor drug release of ATO for HCC therapy. AATONP is prepared by surface embellishment with albumin on the cationic ATO-loaded PEG–PCL–PEI nanoparticles (CATONP). Albumin embellishment can reduce the cationic material’s hemolytic toxicity in blood cells while maintaining the rapid internalization and lysosome escape abilities of the positively charged CATONP. AATONP provides sustained and low pH-responsive drug release, facilitating the targeted drug release in the intratumor acidic microenvironment. Moreover, AATONP can significantly improve the circulation time and tumor distribution of ATO via albumin-mediated transcytosis in HCC tumor-bearing mice. Compared with free ATO and the clinically used nanomedicine Genexol/PM, AATONP shows potent antitumor activity against a human HCC xenograft mouse model, leading to a higher tumor inhibition rate of 89.4% in HCC therapy. In conclusion, this work presents an efficient strategy to achieve tumor accumulation and the intratumor drug release of ATO for HCC therapy.

Graphical abstract

An albumin-embellished arsenic trioxide (ATO)-loaded polyethylene glycol–polycaprolactone–polyethyleneimine nanoparticle (AATONP) is designed to enhance tumor distribution and intratumor drug release of ATO for hepatocellular carcinoma therapy. AATONP can achieve enhanced tumor distribution via albumin-mediated transcytosis and exhibit intratumor drug release of ATO via tumor acidic microenvironment-response, leading to potent antitumor activity.

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Acknowledgments

This work was partially supported by the Natural Science Foundation of China (Nos. 82003669, 82102191), Science and Technology Program on Medicine and Health of Zhejiang Province (Nos. 2017KY511, 2022KY913), and Natural Science Foundation of Zhejiang Province (No. LYY21H310001).

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Author notes

  1. Yu Huang and Zhishi Xu contributed equally to this work.

Authors and Affiliations

  1. Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Yu Huang

  2. Department of Pediatrics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, 310006, China

    Yu Huang & Danfei Chen

  3. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China

    Zhishi Xu, Yinghui Wei, Shunping Han & Danfei Chen

  4. Department of Pharmacy, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310003, China

    Xinjun Cai

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  1. Yu Huang
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Contributions

Yu Huang contributed to investigation, data curation, project administration, methodology, and writing original draft. Zhishi Xu contributed to investigation, validation, software, and writing original draft. Yinghui Wei contributed to conceptualization and validation. Shunping Han contributed to software and writing original draft. Xinjun Cai contributed to conceptualization, funding acquisition, and writing review and editing. Danfei Chen contributed to supervision, funding acquisition, conceptualization, project administration, and writing review and editing.

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Correspondence to Xinjun Cai or Danfei Chen.

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Theme: Recent Advances on Drug Delivery Systems for Viral Infections

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Huang, Y., Xu, Z., Wei, Y. et al. Albumin-Embellished Arsenic Trioxide-Loaded Polymeric Nanoparticles Enhance Tumor Accumulation and Anticancer Efficacy via Transcytosis for Hepatocellular Carcinoma Therapy. AAPS PharmSciTech 23, 111 (2022). https://doi.org/10.1208/s12249-022-02254-4

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